U.S. patent application number 13/362495 was filed with the patent office on 2012-08-02 for process for the preparation of cross-linked polyallylamines or pharmaceutically acceptable salts thereof.
This patent application is currently assigned to CHEMI SPA. Invention is credited to Mauro GABOARDI, Erminio OLDANI.
Application Number | 20120196988 13/362495 |
Document ID | / |
Family ID | 43920015 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120196988 |
Kind Code |
A1 |
GABOARDI; Mauro ; et
al. |
August 2, 2012 |
PROCESS FOR THE PREPARATION OF CROSS-LINKED POLYALLYLAMINES OR
PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
Abstract
The present invention relates to a process for the preparation
of cross-linked polyallylamines or pharmaceutically acceptable
salts thereof. The invention further relates to a process for the
preparation of Sevelamer or pharmaceutically acceptable salts
thereof, preferably hydrochloride or carbonate salts, used in the
treatment of hyperphosphatemia, and having good flowability, low
porosity and/or a swelling index of between 7 and 9.
Inventors: |
GABOARDI; Mauro; (Novara,
IT) ; OLDANI; Erminio; (Cornaredo (MI), IT) |
Assignee: |
CHEMI SPA
Cinisello Balsamo (MI)
IT
|
Family ID: |
43920015 |
Appl. No.: |
13/362495 |
Filed: |
January 31, 2012 |
Current U.S.
Class: |
525/351 ;
525/353 |
Current CPC
Class: |
C08F 26/02 20130101;
A61P 3/12 20180101; C08K 5/42 20130101; C08K 5/0025 20130101; C08K
5/0025 20130101; C08F 20/52 20130101; A61K 31/785 20130101; C08L
39/00 20130101; A61P 39/04 20180101 |
Class at
Publication: |
525/351 ;
525/353 |
International
Class: |
C08J 3/24 20060101
C08J003/24; C08G 73/02 20060101 C08G073/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 1, 2011 |
IT |
MI2011A000126 |
Claims
1. A process for the preparation of cross-linked polyallylamines or
pharmaceutically acceptable salts thereof, which comprises the
following steps: a) polymerizing an allylamine of formula (II)
##STR00011## in the presence of a radical initiator, in an acid
environment, in a polar solvent or a mixture of polar solvents to
give a polyallylamine; b) cross-linking the polyallylamine obtained
in step a) in a basic environment with a cross-linking agent of
formula (III) ##STR00012## in which R is a C.sub.1-C.sub.6 alkyl
group, or an aryl group optionally substituted with one or more
alkyl groups and/or electron-attractor groups, in a polar solvent
or a mixture of polar solvents to give a polymer; c) salifying the
polymer obtained in step b), preferably with a pharmaceutically
acceptable salt; and, d) optionally converting the salified polymer
into another pharmaceutically acceptable salt.
2. A process according to claim 1, wherein the radical initiator is
selected from nitrogenous compounds, preferably
azobisisobutyronitrile, 2,2'-azobis(2-amidinopropane)
dihydrochloride, or
2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride, organic
peroxides, preferably benzoyl peroxide, di-tert-amyl peroxide,
dicumyl peroxide, isopropylbenzene peroxide, inorganic peroxides,
preferably hydrogen peroxide, sodium peroxide, potassium peroxide,
compounds that can be activated by thermal or redox reactions, or a
combination thereof, more preferably, the radical initiator is a
nitrogenous compound, even more preferably
2,2'-azobis(2-amidinopropane) dihydrochloride or
2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride.
3. A process according to claim 1, wherein the molar ratio of
allylamine to radical initiator is between 20:1 and 50:1,
preferably between 20:1 and 35:1.
4. A process according to claim 1, wherein the polymerization
reaction of step a) is performed in the presence of an inorganic
acid, preferably hydrochloric acid, hydrobromic acid, sulphuric
acid, nitric acid, or phosphoric acid, more preferably hydrochloric
acid.
5. A process according to claim 1, wherein the polar solvent is
selected from water, an ester, preferably ethyl acetate or butyl
acetate, a nitrile, preferably acetonitrile, an ether, preferably
tetrahydrofuran or dioxane, an amide, preferably dimethylformamide
or dimethylacetamide, a sulphoxide, preferably dimethylsulphoxide,
or mixtures thereof, more preferably water.
6. A process according to claim 1, wherein the polymerization
temperature of step a) is between the decomposition temperature of
the radical initiator and the reflux temperature of the reaction
mixture, preferably between 60 and 80.degree. C.
7. A process according to claim 1, wherein the R group of the
cross-linking agent of formula (III) of step b) ##STR00013## is
selected from methyl, trifluoromethyl, p-tolyl, and m-nitro-phenyl,
preferably m-nitro-phenyl or p-tolyl.
8. A process according to claim 7, wherein the cross-linking agent
of formula (III) is m-nitrobenzenesulphonyl glycidol or tosyl
glycidol.
9. A process according to claim 1, wherein the cross-linking agent
of formula (III) is added to the polyamine of step a) in solid form
or in solution, preferably in solution in a polar solvent, more
preferably in solution in water or ethyl acetate.
10. A process according to claim 1, wherein the concentration of
the cross-linking agent of formula (III) in solution is between 0.5
and 2 mol/l, preferably between 1.2 and 1.8 mol/l.
11. A process according to claim 1 wherein the cross-linking
reaction of step b) is performed in the presence of a base,
preferably an inorganic base, more preferably sodium or potassium
hydroxide, or sodium or potassium carbonate, even more preferably
sodium hydroxide.
12. A process according to claim 1, wherein the salification of
step c) takes place by treatment with an acid, preferably a
pharmaceutically acceptable acid, more preferably an inorganic
acid, even more preferably hydrochloric acid.
13. A process according to claim 1, wherein the pharmaceutically
acceptable salt of step d) is carbonate.
14. A process according to claim 1, wherein at least one, and even
more preferably all, of steps a), b), c) and d) of the process of
the present invention are performed in "one pot".
15. A process according to claim 1 wherein the cross-linked
polyallylamine is Sevelamer and that the pharmaceutically
acceptable salts thereof are hydrochloride or carbonate salts.
16. Sevelamer or pharmaceutically acceptable salts thereof,
preferably hydrochloride or carbonate salts, obtainable by means of
the process of claim 1.
17. Sevelamer or pharmaceutically acceptable salts thereof
according to claim 16, characterized by an angle of rest of between
25.0.degree. and 27.0.degree. and/or a true density of between 1.25
and 1.32 and/or a swelling index of between 7 and 9.
Description
[0001] The present invention relates to a process for the
preparation of cross-linked polyallylamines or pharmaceutically
acceptable salts thereof. The invention also relates to a process
for the preparation of Sevelamer, or pharmaceutically acceptable
salts thereof, preferably hydrochloride or carbonate salts, used in
the treatment of hyperphosphatemia, and having good flowability,
low porosity and/or a swelling index of between 7 and 9.
FIELD OF THE INVENTION
[0002] Hyperphosphatemia often accompanies diseases connected with
renal insufficiency which is an ever more widespread chronic
condition associated with a progressive loss of kidney function
which often complicates the course of other diseases such as
diabetes and cardiovascular diseases. Particularly when it is
present for long periods of time, hyperphosphatemia leads to
serious anomalies in the metabolism of phosphorus and calcium,
causing calcification of the soft tissues, for example, joints,
lungs, eyes, vessels, arteries, etc.
[0003] Hyperphosphatemia is generally treated with phosphate group
binders such as anion-exchange polymers. These polymers lead to a
reduction in the blood phosphate level without increasing the
absorption of other clinically undesirable compounds. Cross-linked
polyallylamines, Sevelamer for example, are amongst the
anion-exchange polymers that are used widely in the treatment of
hyperphosphatemia. Sevelamer, which is polyallylamine cross-linked
with epichlorohydrin, was marketed initially as the hydrochloride
and more recently, as the carbonate. Sevelamer carbonate has
similar efficacy to Sevelamer hydrochloride but is better tolerated
by patients.
[0004] Sevelamer is a compound of structural formula (I),
##STR00001##
and empirical formula (Ia):
[(C.sub.3H.sub.7N).sub.a+b.(C.sub.9H.sub.17N.sub.2O).sub.c].sub.m
in which: [0005] a+b:c=9:1; [0006] m is a whole number.
[0007] It is described in European patent EP716606B1 and marketed
under the name Renvela.RTM. (Sevelamer carbonate) and Renagel.RTM.
(Sevelamer hydrochloride).
[0008] Few documents describe the preparation of Sevelamer.
European patent EP716606B1 describes the preparation of Sevelamer
hydrochloride by the polymerization of allylamine in the presence
of an initiator, and subsequent cross-linking with
epichlorohydrin.
[0009] European patent EP1175451B1 describes the preparation of
Sevelamer by the reaction of polyallylamine and a cross-linking
agent such as epichlorohydrin or 1,3-dichloro-2-propanol, in a
basic environment, in water and in a water-miscible solvent.
[0010] Patent application WO2009/010531 describes the preparation
of Sevelamer by the reaction of allylamine with
1,3-bis-allylamino-2-propanol as cross-linking agent. Patent
application WO2009/125433 describes the preparation of Sevelamer
carbonate by cross-linking of polyallylamine carbonate with
epichlorohydrin, optionally in the presence of an emulsifier and/or
surfactant. Polyallylamine carbonate is obtained by basic treatment
of polyallylamine hydrochloride and subsequent reaction with a
carbonate source.
[0011] Patent application WO2001/18073 describes the preparation of
Sevelamer with low cohesiveness which is achieved only after
several steps which provide for the reaction of an aqueous
polyallylamine solution with a cross-linking agent such as
epichlorohydrin, washing of the aqueous solution with an
alcohol/water solution in the presence of a surfactant, drying of
the cross-linked polymer, grinding, and finally sieving.
[0012] Patent application WO 01/05408 describes the reaction of
polyallylamines with "modifying agents" for the preparation of
polyallylamine derivatives in which the nitrogen atoms of the amine
groups are bound to hydrophobic substituents of the modifying
agents. In particular, WO 01/05408 describes the use of glycidol as
modifying agent. The reaction of the polyallylamine with glycidol
does not, however, enable it to be cross-linked, as shown in
Comparative Example 6 of the present application.
[0013] There is therefore still a need to provide a process for the
preparation of cross-linked polyallylamines or pharmaceutically
acceptable salts thereof which is repeatable, can easily be
industrialized, without the use of toxic reagents, and which
permits the direct production of cross-linked polyallylamines or
pharmaceutically acceptable salts thereof with good flowability
and/or low porosity, without further process steps such as, for
example, grinding, lyophilization, or spray-drying.
SUMMARY OF THE INVENTION
[0014] It has now surprisingly been found that cross-linked
polyallylamines or pharmaceutically acceptable salts thereof can be
produced by a simple process that can be used at an industrial
level to produce large quantities of product without the use of
toxic reagents and without further process steps.
[0015] The present invention thus relates to a process for the
preparation of cross-linked polyallylamines or pharmaceutically
acceptable salts thereof which comprises the following steps:
a) polymerization of allylamine of formula (II)
##STR00002##
in the presence of a radical initiator, in an acid environment, in
a polar solvent or a mixture of polar solvents to give a
polyallylamine; b) cross-linking of the polyallylamine obtained in
step a) in a basic environment with a cross-linking agent of
formula (III)
##STR00003##
in which R is a C.sub.1-C.sub.6 alkyl group, or an aryl group
optionally substituted with one or more alkyl groups and/or
electron-attractor groups, in a polar solvent or a mixture of polar
solvents to give a polymer; c) salification of the polymer obtained
in step b), preferably with a pharmaceutically acceptable salt; and
d) optional conversion of the salified polymer obtained in step c)
into another pharmaceutically acceptable salt.
[0016] A further aspect of the present invention relates to the
preparation of Sevelamer, or pharmaceutically acceptable salts
thereof, preferably hydrochloride or carbonate salts. Finally, a
subject of the present invention is Sevelamer or pharmaceutically
acceptable salts thereof, preferably hydrochloride or carbonate
salts, obtainable by the above-mentioned process and, in
particular, Sevelamer or pharmaceutically acceptable salts thereof,
preferably hydrochloride or carbonate salts, having an angle of
rest of between 25.0.degree. and 27.0.degree. and/or a true density
of between 1.25 and 1.32 and/or a swelling index of between 7 and
9.
DETAILED DESCRIPTION OF THE INVENTION
[0017] All of the terms that are used in the present application
should be understood in their conventional meaning as they are
known in the art unless indicated to the contrary. Other more
specific definitions for some terms as used in this application are
given below and always apply throughout the description and the
claims unless a different definition explicitly gives a wider
definition.
[0018] The term "polymer" refers not only to a homopolymer but also
to a copolymer.
[0019] The term "polyallylamine" refers to a polymer which
comprises allylamine as a repetitive unit.
[0020] The term "repetitive unit" refers to a part of the polymer
chain which is derived from a single molecule of a monomer.
[0021] The term "cross-linked" refers to interconnections between
the polymer chains.
[0022] The term "cross-linking agent" refers to an accept which
brings about cross-linking, branching, or a combination
thereof.
[0023] The term "C.sub.1-C.sub.6 alkyl" refers to a branched or
linear hydrocarbon containing from 1 to 6 carbon atoms. Examples of
C.sub.1-C.sub.6 alkyl groups include but are not limited to methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, n-pentyl, n-hexyl. The C.sub.1-C.sub.6 alkyl may
optionally be substituted with one or more electron-attractor
groups. The term "aryl" refers to an aromatic carbo-cycle
constituted by 1 or 2 rings fused or bound together by a single
bond. Examples of aryl groups include but are not limited to
phenyl, and .alpha.- or .beta.-naphthyl. The aryl group may
optionally be substituted with one or more C.sub.1-C.sub.6 alkyl
groups e/o electron-attractor groups.
[0024] The term "electron-attractor group" refers to a group which
tends to stabilize carbanions by helping to disperse their negative
charge. Examples of electron-attractor groups include but are not
limited to, halogens, such as fluoro, chloro, bromo, iodo groups;
the nitro group (NO.sub.2); and the nitrile group (CN).
[0025] The term "pharmaceutically acceptable salts" refers to
non-toxic inorganic or organic salts. Examples of pharmaceutically
acceptable salts include but are not limited to: carbonate,
hydrochloride, hydrobromide, sulphate, hydrogen sulphate, citrate,
maleate, fumarate, trifluoroacetate, 2-naphthalenesulphonate, and
para-toluenesulphonate. Further information on pharmaceutically
acceptable salts can be found in pharmaceutical chemistry manuals,
for example: Handbook of pharmaceutical salts, P. Stahl, C.
Wermuth, WILEY-VCH (Eds., 2008, pp. 127-133). The term "one pot"
refers to two or more consecutive reactions which are carried out
without isolating the respective intermediate product or
products.
[0026] The term "approximately" includes the range of the
experimental error which may occur in a measurement. The present
invention relates to a process for the preparation of cross-linked
polyallylamines or pharmaceutically acceptable salts thereof which
comprises the following steps:
a) polymerization of allylamine of formula (II)
##STR00004##
in the presence of a radical initiator, in an acid environment, in
a polar solvent or a mixture of polar solvents to give a
polyallylamine; b) cross-linking of the polyallylamine obtained in
step a) in a basic environment with a cross-linking agent of
formula (III)
##STR00005##
in which R is a C.sub.1-C.sub.6 alkyl group, or an aryl group
optionally substituted with one or more alkyl groups and/or
electron-attractor groups, in a polar solvent or a mixture of polar
solvents to give a polymer; c) salification of the polymer obtained
in step b), preferably with a pharmaceutically acceptable salt;
and, d) optional conversion of the salified polymer into another
pharmaceutically acceptable salt.
[0027] A further aspect of the present invention relates to the
preparation of Sevelamer, or pharmaceutically acceptable salts
thereof, preferably hydrochloride or carbonate salts. Another
aspect of the present invention relates to Sevelamer or
pharmaceutically acceptable salts thereof, preferably hydrochloride
or carbonate salts, obtainable by the process of the present
invention and preferably having an angle of rest of between
25.0.degree. and 27.0.degree. and/or a true density of between 1.25
and 1.32 and/or a swelling index of between 7 and 9.
[0028] Preferably, at least one and, even more preferably, all of
steps a), b), c) and d) of the process of the present invention are
carried out in "one pot".
[0029] The allylamine of formula (II) is polymerized in the
presence of a radical initiator in an acid environment in a polar
solvent or a mixture of polar solvents.
[0030] Any radical initiator known to persons skilled in the art
may be used in the present invention. The radical initiator is
preferably selected from nitrogenous compounds, more preferably
azobisisobutyronitrile, 2,2'-azobis(2-amidinopropane)
dihydrochloride, or
2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044);
organic peroxides, more preferably benzoyl peroxide, di-tert-amyl
peroxide, dicumyl peroxide, isopropylbenzene peroxide; inorganic
peroxides, more preferably hydrogen peroxide, sodium peroxide, or
potassium peroxide; compounds that can be activated by thermal or
redox reactions, or a combination thereof; more preferably, the
radical initiator is a nitrogenous compound, even more preferably
2,2'-azobis(2-amidinopropane) dihydrochloride .smallcircle.
2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride
(VA-044).
[0031] The molar ratio of allylamine to radical initiator is
preferably between 20:1 and 50:1, more preferably between 20:1 and
35:1.
[0032] The polymerization reaction of step a) is performed in the
presence of an acid. The acid is preferably an inorganic acid, more
preferably hydrochloric acid, hydrobromic acid, sulphuric acid,
nitric acid, phosphoric acid, or the like. Even more preferably, it
is hydrochloric acid. Any polar solvent known to persons skilled in
the art may be used in the process of the present invention. The
polar solvent is preferably selected from water; an ester, more
prefer ethyl acetate or butyl acetate; an ester, more preferably
acetonitrile; an ether, more preferably tetrahydrofuran or dioxane;
an amide, more preferably dimethylformamide or dimethylacetamide; a
sulphoxide, more preferably dimethylsulphoxide, or mixtures
thereof, even more preferably water.
[0033] The polymerization reaction is performed at a temperature
such that the reaction goes to completion, preferably at a
temperature between the decomposition temperature of the radical
initiator and the reflux temperature of the reaction mixture, more
preferably between 60 and 80.degree. C.
[0034] The polyallylamine thus obtained can be isolated by
separation techniques well known to persons skilled in the art,
such as: extraction, filtration, crystallization, precipitation,
and the like, or it may be used directly, without isolation or
purification, in the subsequent cross-linking step b). The
polyallylamine is preferably not isolated.
[0035] After the pH of the polymerization mixture of step a) has
been brought to basic values by the addition of a base, the
polyallylamine is reacted with the cross-linking agent of formula
(III)
##STR00006##
in which R is a C.sub.1-C.sub.6 alkyl group, or an aryl group
optionally substituted with one or more alkyl groups and/or
electron-attractor groups. Preferably, R is selected from methyl,
trifluoromethyl, p-tolyl, and m-nitro-phenyl; more preferably
m-nitro-phenyl or p-tolyl. The cross-linking agent of formula (III)
is preferably m-nitrobenzensulphonyl glycidol or tosyl
glycidol.
[0036] The cross-linking reaction of step b) is performed in the
presence of a base. Any base known to persons skilled in the art
may be used in the present invention to bring the pH of the
solution to basic values. Preferably, the base is an inorganic
base, more preferably sodium or potassium hydroxide or sodium or
potassium carbonate, even more preferably sodium hydroxide.
[0037] The cross-linking agent of formula (III), in solid form or
in solution, is added to the polyallylamine solution. Any polar
solvent or mixture of polar solvents known to persons skilled in
the art may be used in the present invention. Preferably, the
compound of formula (III) is used in solution in a polar solvent,
more preferably water, even more preferably ethyl acetate.
[0038] The concentration of the cross-linking agent of formula
(III) is preferably between 0.5 and 2 mol/l, more preferably
between 1.2 and 1.8 mol/l.
[0039] The cross-linking agent of formula (III) may be prepared by
any method known to persons skilled in the art, for example, as
described in J. Org. Chem., 1989, 54, 1295-1304. For example, the
compound of formula (III) may be prepared as shown by way of
example in Scheme 1, by reacting the glycidol of formula (IV),
which is a commercial product, with the sulphonyl halide
R--SO.sub.2X of formula (V) in which R has the meaning defined
above and X is a halogen, for example, chlorine, bromine, or
iodine. The reaction takes place in a basic environment, preferably
with the use of an organic base such as an amine, for example,
triethylamine or diisopropylethylamine; an amidine, for example,
1,8-diazadicyclo[5,4,0]undec-7-ene; or an aromatic base, for
example, pyridine. More preferably, the base is triethylamine or
diisopropylethylamine.
##STR00007##
[0040] The compound of formula (III) may be isolated in accordance
with techniques well known to persons skilled in the art such as,
for example, extraction, filtration, crystallization,
precipitation, and the like, or may be used without further
separation and purification, by adding the solution containing it
directly to the polyallylamine mixture. After the addition of the
cross-linking agent of formula (III), the reaction mixture is
preferably stirred for 6-14 hours, more preferably 10-12 hours. An
easily handled, solid polymer is obtained. The reaction mixture is
then brought to acid pH by the addition of an acid to give the
salified polymer.
[0041] Any acid known to persons skilled in the art may be used in
the present invention to salify the polymer. Preferably, the acid
is a pharmaceutically acceptable acid, more preferably an inorganic
acid, even more preferably hydrochloric acid. The salified polymer
can be isolated by techniques known to persons skilled in the art,
such as precipitation, filtration, with or without pressure and/or
under vacuum, crystallization, centrifuging, decantation, and the
like. Preferably, the salified polymer is a hydrochloride or a
carbonate, more preferably a carbonate.
[0042] Any method known to persons skilled in the art may be used
to obtain the polymer carbonate. Preferably, the polymer
hydrochloride is converted into the corresponding carbonate by
reaction with a carbonate source. Preferably, according to an
aspect of the invention, the polymer hydrochloride is suspended in
water and a carbonate source, for example, sodium or potassium
carbonate, preferably sodium carbonate, is added. The reaction
mixture is brought to a suitable temperature between room
temperature and the reflux temperature of the reaction mixture,
preferably between room temperature and 40.degree. C. The polymer
in the form of the carbonate salt is separated from the mother
liquor, washed and dehydrated.
[0043] The process of the present invention permits the preparation
of cross-linked polyallylamines or pharmaceutically acceptable
salts thereof, preferably Sevelamer or pharmaceutically acceptable
salts thereof, more preferably hydrochloride or carbonate salts,
even more preferably the carbonate salt.
[0044] The process of the present invention is an efficient,
inexpensive process with good yields, is repeatable, and takes
place in very mild conditions without the use of surfactants and/or
toxic substances. The process of the present invention can easily
be used on an industrial scale to prepare large quantities of
product and enables the final product to be produced with
well-defined chemical and physical characteristics which lead to
easy handling of the solid obtained, without the need for further
processes such as grinding, lyophilization, or spray-drying.
[0045] In the pharmaceutical field, the flowability of the powder
and the true density of the product are factors which are extremely
important for ease of handling of the solid, for optimal storage,
and for the preparation of pharmaceutical formulations.
[0046] Sevelamer and the pharmaceutically acceptable salts thereof
such as the hydrochloride and carbonate salts which can be obtained
by the process of the present invention have good flowability, good
porosity, and/or a swelling index of between 7 and 9.
[0047] The flowability a powder is determined by measurement of the
corresponding angle of rest. The angle of rest measured on
Sevelamer or the pharmaceutically acceptable salts thereof that are
obtained by the process described in the present invention is
between 25.0.degree. and 27.0.degree..
[0048] The angle of rest was measured in accordance with the method
described in European Pharmacopoeia 6.0 (2010); 100 g of product
were introduced into a hopper having a blocked hole placed 10 cm
from a surface. The hole was opened, the powder was allowed to flow
out, and the flow time was measured.
[0049] The porosity of a powder is determined by measurement of its
true density. A high true density indicates low porosity, given
that there are fewer empty interstitial spaces.
[0050] Sevelamer and the pharmaceutically acceptable salts thereof
such as the hydrochloride and carbonate salts which can be obtained
by the process described in the present invention have a true
density of between 1.25 and 1.32.
[0051] The true density was measured in accordance with the helium
pycnometry method as described in the ASTM B923-02 "Standard Test
Method for Metal Powder Skeletal Density by Helium or Nitrogen
Pycnometry".
[0052] Sevelamer and the pharmaceutically acceptable salts thereof
such as the hydrochloride and carbonate salts which can be obtained
by the process described in the present invention have a swelling
index of between 7 and 9.
[0053] A high swelling index means that the polymer incorporates
water until it adopts a volume equal to the value of the index. The
swelling index was measured in accordance with the procedure
described in patent WO 01/18073 which is incorporated herein by
reference.
[0054] The phosphate sequestering power of Sevelamer and the
pharmaceutically acceptable salts thereof such as the hydrochloride
and carbonate salts which can be obtained by the process described
in the present invention is between 5.0 and 6.0 mmol/g.
[0055] In a preferred embodiment of the present invention, in order
to obtain Sevelamer or the pharmaceutically acceptable salts
thereof, the allylamine polymerization reaction is performed with
the use, as radical initiator, of
2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044)
in a molar ratio of allylamine to radical initiator of
approximately 23:1 and hydrochloric acid as the acid. The polar
solvent used is water. The polymerization reaction is performed at
a temperature of 30-50.degree. C., preferably approximately
40.degree. C.
[0056] The reaction for the cross-linking of the polyallylamine
thus obtained is performed in a basic environment by the addition
of sodium hydroxide and one of the cross-linking agents of formula
(IIIa) or (IIIb) given below, that is, tosyl glycidol or
m-nitrobenzensulphonyl glycidol, respectively, in ethyl
acetate.
##STR00008##
[0057] The reaction takes approximately 10-12 hours.
[0058] The pH is then brought by the addition of hydrochloric acid.
The solid thus obtained, which corresponds to Sevelamer
hydrochloride, is suspended in water and sodium carbonate is added.
The temperature is brought to approximately 30-35.degree. C. After
washing with isopropanol, Sevelamer carbonate is obtained.
[0059] Even though characteristic aspects of the present invention
have been described, modifications and equivalents that are clear
to persons skilled in the art are included in the present
invention.
[0060] The present invention will be illustrated below by means of
some examples which should not be seen as limiting of the scope of
the invention.
EXAMPLES
[0061] The following abbreviations refer to the definitions given
below, respectively:
[0062] AcOEt (ethyl acetate); TEA (triethylamine); TLC (Thin Layer
Chromatography); HCl (hydrochloric acid); h (hour); r.t. (room
temperature); VA-044
(2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride).
Example 1
Synthesis of Tosyl Glycidol (IIIa)
##STR00009##
[0064] AcOEt (800 ml) and TEA (162.72 g, 1.61 mol) were introduced
into a 2 litre, 3-necked flask with a magnetic stirrer,
thermometer, and cooler and tosyl chloride (286 g, 1.5 mol) was
added in portions. The internal temperature was brought to
0.degree. C. and glycidol (IV) was added dropwise over a period of
1 h. The mixture was left to react overnight and was allowed to
return slowly to r.t. The reaction was monitored by TLC
(hexane/AcOEt 8:2). Upon completion of the reaction, 250 ml of
H.sub.2O were added and two clear phases were obtained. The phases
were separated and the organic phase was washed with 100 ml of
H.sub.2O containing approximately 10 g of NaCl. Dehydration was
performed with sodium sulphate AcOEt was evaporated. The pure tosyl
glycidol (IIIa) was obtained as a brilliant white, low melting,
waxy solid (370 g). Yield: 96%.
[0065] .sup.1H-NMR (CDCl.sub.3, 200 MHz): 7.791 (d 2H); 7.344 (d
2H); 4.23 (dd 1H); 3.937 (dd 1H); 3.167 (m 1H); 2.798 (m 1H); 2.575
(m 1H); 2.439 (s 3H).
Example 2
Synthesis of m-Nitrobenzenesulphonyl Glycidol (IIIb)
##STR00010##
[0067] AcOEt (20 ml) and TEA (2.53 g, 0.025 mol) were introduced
into a 50 ml, 3-necked flask with a magnetic stirrer, thermometer,
and cooler and m-nitrobenzenesulphonyl chloride (5 g, 0.0226 mol)
was added in portions. The internal temperature was brought to
0.degree. C. and glycidol (IV) (1.84 g, 0.025 mol) was added
dropwise over a period of 1 h. The mixture was left to react
overnight and was allowed to return slowly to r.t. The reaction was
monitored by TLC (hexane/AcOEt 8:2). Upon completion of the
reaction, 10 ml of H.sub.2O was added and two clear phases were
obtained. The phases were separated and the organic phase was
washed with 10 ml of H.sub.2O containing approximately 1 g of NaCl.
Dehydration was performed with sodium sulphate and the AcOEt was
evaporated. Pure m-nitrobenzenesulphonyl glycidol (IIIb) was
obtained as a brownish-yellow, low melting, waxy solid (4.6 g).
Yield: 78.6%.
[0068] .sup.1H-NMR (CDCl.sub.3; 300 MHz): 8.75 (d 1H); 8.52 (dd,
1H); 8.2.4 (dd 1H); 7.81 (t 1H); 4.45 (dd 1H); 4.03 (dd 1H); 3.20
(m 1H); 2.83 (m 1H); 2.61 (m 1H).
Example 3
Preparation of Sevelamer Hydrochloride with the Use of Tosyl
Glycidol (IIIa) as Cross-Linker
[0069] 37% HCl (38 g, 0.385 mol) was introduced into a 250 ml,
4-necked flask with a mechanical stirrer, cooler, and thermometer
and diluted with water (24 ml). The temperature was brought to
2-4.degree. C. and allylamine (20 g, 0.35 mol) was added dropwise.
Upon completion of the dropwise addition, the temperature was
brought to 72-73.degree. C. During the heating, at approximately
40.degree. C., the VA-044 initiator (4.8 g, 0.015 mol) was added.
The mixture was left to react for 4 h. The aqueous solution was
clear and the viscosity increased over time. The solution was
brought to pH 10 with 50% NaOH and the solution of tosyl glycidol
(Ma) in AcOEt (20 g, 0.0877 mol in 50 ml) was added dropwise. The
addition was performed over a period of 1 hour. The mixture was
left to react overnight and a gelatinized product was obtained.
Further AcOEt (80 ml) was added. The mixture was brought to acid pH
with 37% HCl and filtered through cloth. The solid was washed with
a water/isopropanol mixture (2.times.250 ml) and with isopropanol
(2.times.250 ml). 50 g of a moist solid was obtained. The solid was
dried in an oven to give 38 g of still moist Sevelamer
hydrochloride which was used unchanged in the next step.
Example 4
Preparation of Sevelamer Carbonate
[0070] Sevelamer hydrochloride (28 g) was suspended in water (420
ml). Sodium carbonate (17.5 g, 0.165 mol) was added during
stirring. The temperature was brought to 30-35.degree. C. and
stirring was continued for approximately 30 minutes. 200 ml of
isopropanol was added and the mixture was filtered in a Buchner
filter. The solid was washed with a (1:1) water/isopropanol mixture
(2.times.250 ml) and with isopropanol (250 ml). 35 g of a moist
solid was obtained. The product was dried in an oven under vacuum
giving 16 g of Sevelamer carbonate.
Example 5
Preparation of Sevelamer with the Use of m-Nitrobenzenesulphonyl
Glycidol (IIIb) as Cross-Linker
[0071] 37% HCl (4.8 g, 0.0487 mol) was introduced into a 3-necked,
50 ml flask with a magnetic stirrer, cooler, and thermometer and
was diluted with H.sub.2O (2 ml). The temperature was brought to
2-4.degree. C. and allylamine (2.53 g, 0.0443 mol) was added
dropwise. Upon completion of the dropwise addition, the temperature
was brought to 72-73.degree. C. During the heating, at
approximately 40.degree. C., the VA-044 initiator (0.62 g, 0.0019
mol) was added. The mixture was left to react for 4 h. The aqueous
solution was clear and the viscosity increased over time. When the
4 h had elapsed, the excess water (approximately 15 ml) was
distilled, the solution was brought to pH 10 with 50% NaOH (2 g)
and the solution of m-nitrobenzenesulphonyl glycidol (IIIb) in
AcOEt (4.3 g, 0.0166 mol in 11 ml) was added dropwise. The addition
was performed over a period of approximately 1 hour. The mixture
was left to react for 14 hours at 70.degree. C. Gelatinization was
observed after only half an hour. A further 80 ml of AcOEt was
added to improve the breaking-up of the product. The mixture was
brought to acid pH with 37% HCl and filtered through cloth. The
solid was washed with a water/isopropanol mixture (3:1) (2.times.50
ml) and with isopropanol (3.times.50 ml). The product was dried in
an oven at 60.degree. C. to give 6.68 g of Sevelamer
hydrochloride.
Example 6 (Comparative)
Preparation of Sevelamer Hydrochloride with the Use of Glycidol as
Cross-Linker
[0072] 37% HCl (3.49 g, 0.0957 mol) was introduced into a 4-necked,
100 ml flask with a mechanical stirrer, cooler, and thermometer and
diluted with water (6 ml). The temperature was brought to
2-4.degree. C. and allylamine (4.97 g, 0.0870 mol) was added
dropwise. Upon completion of the dropwise addition, the temperature
was brought to 72-73.degree. C. During the heating, at
approximately 40.degree. C., the VA-044 initiator (1.21 g, 0.00373
mol) was added. The mixture was left to react for 4 h. The aqueous
solution was clear and the viscosity increased over time. The
solution was brought to pH 10 with 50% NaOH and the solution of
glycidol in AcOEt (1.61 g, 0.0218 mol in 12.5 ml) was added
dropwise. The addition was carried out over a period of 1 hour. The
mixture was left to react overnight and the formation of Sevelamer
was not noted since an emulsion was obtained which, upon the
addition of water, gave rise to a clear, and hence polymer-free,
solution.
* * * * *